Patients diagnosed with advanced pancreatic ductal adenocarcinoma (PDAC) have a 5 year survival rate of less than 5%. These tumors have the highest reported incidence of KRAS mutations among all human cancers. Because of these observations, there has been considerable interest in developing direct inhibitors of RAS mutants such as KRAS. However, attempts to directly inhibit KRAS have to date been unsuccessful. An alternative approach is to target downstream effectors of KRAS on the MAPK pathway. Extracellular Regulated Kinase 1 and 2 (ERK 1/2) are serine-threonine protein kinases which are downstream components of the RAS/RAF/MEK signal transduction pathway. Aberrant activation of ERK has been demonstrated in many human tumors, including pancreatic cancer. ERK inhibitors could prove very useful as therapies to treat tumors with RAS mutations such as PDAC. This proposal aims to determine the potential of Kalyra's novel ERK inhibitors as treatments for PDAC via the following aims. Phase 1: Characterization of Novels Leads in Models of Pancreatic Cancer Aim 1. Evaluate 10 lead molecules in preliminary in vitro ADME and Plasma Protein Binding studies. Aim 2. Confirm efficacy of 5 lead molecules vs. a panel of human RAS mutant pancreatic cancer cell lines. Aim 3. Determine PK and in vivo efficacy of top 3 leads in an in vivo model of KRAS pancreatic cancer. Phase II: Additional studies to enable selection of a Development Candidate Aim 1. Characterize the effects of lead ERK inhibitors in combination studies Aim 2. ADME and Preliminary Toxicology Aim 3. Pharmcokinetics for Species Selection for Toxicology and Pilot Toxicology After completion of the studies outlined in this proposal, we will have selected a drug candidate to enter IND enabling;toxicology studies in support of filing an IND with the FDA to begin human clinical trials for the development of a novel effective treatment for pancreatic ductal adenocarcinoma.